Journal Article

HBV-associated hepatocellular carcinomas inhibit antitumor CD8+ T cell via the long noncoding RNA HDAC2-AS2

Yang, Fuquan, Ding, Xiang, Chen, Runsheng, Wang, Kang, Li, Nan, Cheng, Shu-qun, Huang, Xuetao, Luo, Jianjun, Du, Chengzhi, You, Maojun, Gao, Yanan, Zhang, Zhenxing, Hao, Yajing, Yang, Pengyuan

2025

Overview

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Extracellular vesicles (EV) are critical mediators of intercellular communication within the tumor microenvironment, and cancer-cell-secreted EVs often facilitate cancer progression. Here we show that in HBV-associated HCC, tumor-cell-derived EVs contain a TGFβ-inducible long noncoding RNA, termed HDAC2-AS2 . EVs enriched with HDAC2-AS2 facilitate cancer progression by suppressing cytotoxicity of intra-tumor CD8 + T cells. Mechanistically, in activated cytotoxic CD8 + T cells, translocation of the transcription factor cyclin-dependent kinase 9 (CDK9), to the cytoplasm is critical for functional integrity. HDAC2-AS2 targets and blocks cytosolic CDK9, and this results in exhaustion of PD-1 + CD8 + T cells and suppression of IFN-γ + CD8 + T cell cytotoxicity. Notably, we demonstrate that low CDK9 and high HDAC2-AS2 expressions are associated with poor survival of HCC, which can be rescued by anti-PD-1 therapy. These findings emphasize the significance of tumor-derived EVs in suppressing antitumor CD8 + T cell immunity to promote tumorigenesis, and highlight extracellular HDAC2-AS2 as a promising biomarker and therapeutic target for HCC. Here authors show that EVs derived from hepatocellular carcinomas may contain the long noncoding RNA, HDAC2-AS2, which suppresses antitumour CD8 + T cells by interfering with transcriptional and epigenetic regulation of their activated, cytotoxic functional state.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/31 / 13/44 / 13/89 / 13/95 / 14/28 / 38/61 / 38/77 / 49 / 631/250/1619/554/1834/1269 / 631/250/580/1884/2323 / 631/67/327 / 64 / 692/4028/67/1504/1610/4029 / Animals / Biomarkers / Cancer / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - immunology / Carcinoma, Hepatocellular - pathology / Carcinoma, Hepatocellular - virology / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell Line, Tumor / Cyclin-dependent kinase / Cyclin-Dependent Kinase 9 / Cyclin-dependent kinases / Cytoplasm / Cytotoxicity / Epigenetics / Female / Gene Expression Regulation, Neoplastic / Gene regulation / HDAC2 protein / Hepatitis B virus - immunology / Hepatocellular carcinoma / Histone deacetylase / Histone Deacetylase 2 - genetics / Histone Deacetylase 2 - metabolism / Humanities and Social Sciences / Humans / Kinases / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - immunology / Liver Neoplasms - pathology / Liver Neoplasms - virology / Lymphocytes / Lymphocytes T / Male / Malignancy / Mice / multidisciplinary / Non-coding RNA / PD-1 protein / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Programmed Cell Death 1 Receptor - metabolism / RNA, Long Noncoding - genetics / RNA, Long Noncoding - immunology / RNA, Long Noncoding - metabolism / Science / Science (multidisciplinary) / Therapeutic targets / Toxicity / Translocation / Tumor microenvironment / Tumor Microenvironment - immunology / Tumorigenesis / Tumors / γ-Interferon